Connective tissue is a complex of several macromolecules, each with its own specific inherited molecular characteristics and biosynthetic processing. A molecular defect in one component of the matrix could lead to defective interactions at many levals either because specific binding between extracellular molecules has been altered or because feedback regulation of biosynthesis has resulted in alterations of the intracellular processing and extracellular quantity for other matrix components. The hypothesis to be tested in these experiments is that altered collagen metabolism results in secondary alterations in proteoglycan metabolism, producing structural and functional changes in the connective tissue complex. In vitro experiments have demonstrated that proteoglycan type and concentration can specifically influence collagen fibrillogenesis. The quantity and type of proteoglycans produced by normal adult dermal explants and skin fibroblast cell lines established from these explants will be determined, in order to provide the baseline for these investigations. The quantity, type, localization, labeling kinetics and turnover of proteoglycans produced by these normal cells will be compared with similar determinations for cells from patients for whom a specific defect in type I or type III collagen structure and metabolism has been associated with decreased secretion of that collagen and connective tissue disease (osteogenesis imperfecta and Ehlers-Danlos syndrome, respectively). The morphology of the insoluble matrix produced by these cells in culture will be described by immunofluorescence microscopy and by electron microscopy. In addition, proteoglycan metabolism will be examined in dermal explant cultures from normal and affected individuals in order to determine whether the alterations noticed in culture are also found in cells in their tissue environment. If no differences are found it will mean that the biosynthetic and transport pathways for collagen and proteoglycans are separate, producing an altered extracellular ratio for these macromolecules that could influence matrix structure. If proteoglycan metabolism is altered in cells with the collagen defects, some type of co-regulation of these molecules will be indicated. Increased understanding of the relationship between collagen and proteoglycans in regulating the formation of a functional connective tissue matrix will be useful in understanding the alterations of connective tissue that accompany much more common conditions, such as normal aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG005582-01
Application #
3116196
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1985-01-01
Project End
1987-12-31
Budget Start
1985-01-01
Budget End
1985-12-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of New Mexico
Department
Type
Schools of Arts and Sciences
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131